Preparation of Spray-dried Emulsion of Sirolimus for Enhanced Oral Bioavailability

摘要

Sirolimus (Rapamycin), a 31-membered macrocyclic lactone derived from Streptomyces hygroscopicus, is an immunosuppressive drug currently used for anti-rejection therapy in organ transplantation. The first commercially available product of sirolimus was an oral solution based on phosphatidylcholine, propylene glycol, and ethanol. Unfortunately, this oral solution is an inconvenient dosage form for patients owing to the requirement for refrigeration and the use of a disposable syringe. To overcome the disadvantages of this solution, an oral tablet form containing sirolimus nanocrystals, developed by using nanocrystal technology, was launched. However, sirolimus is poorly soluble in water and in physiological pH conditions, a BCS Class II drug, and very unstable in solid and solution states owing to degradation via ring opening/fragmentation. A rapid degradation of sirolimus was previously reported in acidic conditions (pH 1.2) compared with that in other conditions (pH 4.0, 6.8, and water). Recently, various drug delivery strategies were reported, such as solid dispersions, liposomes, micelles, nanocrystals, and nanoparticles (polymer and albumin), to improve the biological performance of sirolimus. In particular, our groups reported various formulation strategies, such as solid dispersion nanoparticles, self-microemulsifying systems, micellar systems, supersaturable formulations, and Eudragit E/HCl solid dispersions, to improve the solubility, stability, dissolution, and oral absorption of sirolimus. These formulation strategies provided acceptable enhancement of oral bioavailability compared with commercial products. Furthermore, in vitro dissolution properties were directly correlated with the in vivo pharmacokinetic data. However, the undesired dissolution of sirolimus was observed in acidic dissolution medium owing to the rapid degradation of sirolimus. The dissolution property of sirolimus in acidic conditions still needs to be improved for enhanced oral bioavailability of sirolimus.